Project Summary/Abstract: Immunomodulatory drugs (IMiDs) are a mainstay of myeloma therapy. They work by binding to the substrate recognition surface of the cereblon (CRBN) E3 ubiquitin ligase and, in so doing, alter its substrate specificity such that it now targets the critical myeloma transcription factors IKZF1 and IKZF3 for proteasomal degradation. A majority of patients develop resistance to IMiDs, and in some patients, the myeloma cells fail to make CRBN and become pan-IMiD resistant. Such patients have a very poor prognosis. To address this issue, I have developed a novel positive-selection screen for the identification of small molecule degraders of any protein of interest. As a proof-of-concept, I have applied this screen to IKZF1. I have identified Spautin-1, a novel degrader of IKZF1 that acts via an unknown mechanism that is distinct from that of IMiDs. In Aim 1, I propose to identify the minimal Spautin-1 responsive degron. In Aim 2, I propose complementary genetic and biochemical experiments to identify the proteins necessary for the action of Spautin-1. Aims 1 and 2 should together help elucidate the mechanism of action of Spautin-1. In Aim 3, I propose SAR studies to find Spautin- 1 derivatives with increased potency against IKZF1 and minimal off-target effects, and that destabilize IKZF1 in vitro and in vivo models. These studies will help identify a novel pathway for destabilizing IKZF1, and may yield novel treatments for IMiD-refractory myeloma. Finally, if successful, these studies will point the way towards the eventual application of this strategy to undruggable transcription factors in other neoplasms. I'm a medical oncologist with a research background in cancer biology, applying for a K08 award with the long-term goal of becoming a tenure-track, independent laboratory investigator. I envision developing an independent research program aimed at understanding the pathways that regulate the activity and stability of critical oncogenic transcription factors in hematologic malignancies, and harnessing that knowledge to develop new therapies for patients. During my proposed K08 research training, I will perform mentored research in the lab of Dr. William Kaelin at the Dana-Farber Cancer Institute (DFCI) on the mechanism by which Spautin-1 degrades IKZF1. I will spend 90% of my time on research and 10% on patient care and teaching duties while seeing patients with hematologic malignancies. I have assembled an expert scientific advisory committee to help guide my development including: Dr. Kenneth Anderson (Harvard Medical School, DFCI), Dr. Eric Fischer (DFCI), Dr. Sara Buhrlage (DFCI), and Dr. Wade Harper (HMS). My clinical mentor is Dr. Daniel Deangelo, a national expert on leukemia. I believe that training in a world-class clinical and research environment, along with additional coursework and conferences will help me achieve my long-term career goals.